“All of the sudden, I have this out of the blue urge to sleep.” – Scott

The Neurobiology of Narcolepsy

In narcolepsy, the sleep-wake cycle is unpredictable and unstable.1-5

Insufficient activation of wake-promoting neurons as well as insufficient inhibition of non-REM sleep- and REM sleep-promoting neurons can lead to sleep-wake state instability.1-3,6 The transitions between wakefulness, non-REM sleep, and REM sleep become frequent and unpredictable, and the boundaries between them become unstable, allowing elements of one state to intrude into another.1-3,7,8 Watch to learn more about narcolepsy.

Normal Sleep-Wake Cycle

A normal sleep-wake cycle is generally characterized by consolidated wakefulness during the day and predictable, alternating periods of non-REM and REM sleep at night, with generally infrequent awakenings.4,6,9

Narcolepsy Sleep-Wake Cycle

In narcolepsy, the sleep-wake cycle is unstable throughout a 24-hour period.1-5

Leading to…

Frequent and unpredictable transitions between states1,3,6

Unstable boundaries between states, allowing elements of one state to intrude into another2,6,7

What Causes Narcolepsy?

In people with narcolepsy who experience cataplexy, the disorder is usually caused by the selective loss of hypocretin neurons (hypocretin deficiency).2,12 Patients with hypocretin deficiency are usually diagnosed with narcolepsy with cataplexy (type 1 narcolepsy).12 The presence of cataplexy is generally thought to indicate more significant loss of hypocretin neurons.1,12,13 In people with narcolepsy without cataplexy, the cause is often not known.2,12

Genetic factors play a key role in the development of narcolepsy.2 Up to 98% of patients with narcolepsy have the human leukocyte antigen (HLA) gene variant HLA-DQB1*0602, compared with 12% to 38% of the general population.2,12 The loss of hypocretin-producing neurons is likely triggered by an autoimmune response in genetically predisposed people.2,14

The underlying cause of narcolepsy without cataplexy (often called type 2 narcolepsy) is often not known.2,12 However, 25% to 33% of patients with type 2 narcolepsy also have intermediate to undetectable cerebrospinal fluid (CSF) hypocretin levels.12,15 These individuals are more likely to develop cataplexy and subsequently be diagnosed with type 1 narcolepsy.12,15

In the majority of people with narcolepsy, the loss of hypocretin leads to sleep-wake state instability, allowing elements of non-REM sleep and REM sleep to intrude into wakefulness.1-3 Although histamine may still be present in these individuals, without the wake-promoting and stabilizing effects of hypocretin, physiologic histamine signaling is insufficient to stabilize wakefulness.16,17

Sudden and brief loss of muscle strength or tone, often triggered by strong emotions. Narcolepsy with cataplexy is known as type 1 narcolepsy.

Complete collapse to the ground; all skeletal muscles are involved.

Only certain muscle groups are involved.

Biological clock mechanism that regulates the 24-hour cycle in the physiological processes of living beings. It is controlled in part by the SCN in the hypothalamus and is affected by the daily light-dark cycle.

Frequent inappropriate transitions between states of sleep and wakefulness.

The inability to stay awake and alert during the day.

A neurotransmitter that supports wakefulness. The TMN is the only source of histamine in the brain.